Unlike the impression obtained from crystallographic models of proteins, real protein molecules are not particularly rigid, but may experience internal movements of many kinds. We propose to study two kinds of motions in proteins -- small, non-cooperative, liquid-like motions and larger local unfolding motions -- by determining how these allow small molecules to enter proteins and contact normally buried groups. These encounters will be detected: a) by measurements of the quenching of phosphorescence and fluorescence of particular tryptophans; b) by the OH- catalyzed H-D exchange of buried tryptophan indole NH, monitored by phosphorescence lifetime enhancement; c) by the enhancement of nuclear spin-lattice relaxation (T1) of particular protons due to the presence of incoming O2. Earlier studies suggest that some encounters are mediated by direct penetration processes; such is the case for partitioning by O2, though whether this response represents a superficial penetration or a deeper internal diffusion process remains to be seen. In contrast, the interactions of larger molecules and ionic agents with buried groups in proteins appear to occur by local unfolding reactions. We propose to study a large number of proteins and penetrating agents of varying size, polarity, etc., developed by us in preliminary studies. The experiments are intended to characterize internal protein motions in terms of size, time scale, energetics, dependence on known protein structure, and interaction with protein function.